Method and System of Augmenting Cancer Therapy

Abstract

Following DNA damage events, such as radiation therapy, cytosolic dsDNA species are generated that trigger intrinsic STimulator of Interferon Genes (STING) signaling and render cells competent for phagocytic activation contingent on the chemokine CCL5 (C-C Motif Ligand 5). Loss of STING signaling or inducible CCL5, rendered DNA-damaged cells incapable of APC stimulation following phagocytosis. STING signaling facilitated the generation of immunogenic endosomal vesicles comprising the autophagy related proteins RAB9 and LC3, and cytosolic DNA which triggered APC activation in trans, an event which also required extrinsic cGAS/STING-dependent signaling. Further, the combination of radiation treatment in the presence of type I IFN greatly reduced tumor growth while rescuing the ability to generate CTL activity. Reconstitution of STING signaling and/or the combination of radiation treatment in the presence of type I IFN could significantly augment cancer therapy.

What is claimed is: 
     
         1 . A method of treating cancer in a subject in need thereof comprising administering a radiation therapy to the subject, where the subject has been determined to be responsive to the radiation therapy comprising:
 (a) contacting a sample from the subject comprising one or more nucleic acid molecules with a device comprising a single-stranded nucleic acid molecule capable of specifically hybridizing with nucleotides of a CCL5 gene;   (b) detecting a level of expression of the CCL5 gene by performing microarray analysis or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) of the sample; and   (c) determining that the CCL5 gene is expressed in the subject.   
     
     
         2 . The method of  claim 1 , further comprising augmenting CCL5 production by administering type I interferon to the subject. 
     
     
         3 . The method of  claim 2 , where the type I interferon is administered in a tumor into the subject. 
     
     
         4 . The method of  claim 3 , where the type I interferon is administered in the presence of the radiation therapy. 
     
     
         5 . The method of  claim 3 , where the type I interferon is administered i.p. into the tumor. 
     
     
         6 . The method of  claim 1 , further comprising where type I interferon is expressed in the sample. 
     
     
         7 . A method of treating a cancer in a subject in need thereof comprising:
 (a) contacting a sample from the subject comprising one or more nucleic acid molecules with a device comprising single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of a CCL5 gene;   (b) detecting a level of expression of the CCL5 gene by performing microarray analysis or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) of the sample;   (c) determining that the CCL5 gene is expressed in the subject; and   (d) administering a therapy to the subject thereby providing the method of treating the cancer.   
     
     
         8 . The method of  claim 7 , further comprising augmenting CCL5 production by administering type I interferon to the subject. 
     
     
         9 . The method of  claim 8 , where the type I interferon is administered in a tumor into the subject. 
     
     
         10 . The method of  claim 9 , where the type I interferon is administered in the presence of a radiation therapy. 
     
     
         11 . The method of  claim 9 , where the type I interferon is administered i.p. into the tumor. 
     
     
         12 . The method of  claim 7 , further comprising where type I interferon is expressed in the sample. 
     
     
         13 . The method of  claim 7 , where the therapy is selected from the group consisting of radiation therapy, chemotherapy, immunotherapy and car-T therapy. 
     
     
         14 . A method of treating a cancer in a subject in need thereof comprising:
 (a) contacting a sample from the subject comprising one or more nucleic acid molecules with a device comprising single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of a CCL5 gene;   (b) detecting a level of expression of the CCL5 gene by performing microarray analysis or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) of the sample;   (c) determining that the CCL5 gene is expressed in the subject; and   (d) administering a radiation therapy to the subject thereby providing the method of treating the cancer, where the radiation therapy is administered in a dosage between:   a lower limit of approximately 1 Rad/day; and   an upper limit of approximately 100 Rad/day.   
     
     
         15 . The method of  claim 14 , further comprising augmenting CCL5 production by administering type I interferon to the subject. 
     
     
         16 . The method of  claim 15 , where the type I interferon is administered in a tumor in to the subject. 
     
     
         17 . The method of  claim 15 , where the type I interferon is administered in the presence of the radiation therapy. 
     
     
         18 . The method of  claim 15 , where the type I interferon is administered i.p. into a tumor. 
     
     
         19 . The method of  claim 14 , further comprising where type I interferon is expressed in the sample.